The present invention relates to a novel 4-acylaminopyridine derivative and a pharmaceutically acceptable acid-added salt thereof useful for activating a malfunctioned cholinergic neuron.
As a therapeutic treatment for various disturbances of memory such as Alzheimer's disease characterized by malfunction of a cholinergic neuron, has been made an attempt to increase the acetylcholine content in the brain by using an antiacetylcholinesterase. For example, investigation on the use of physostigmine is reported in Neurology, 8, 397(1978). Japanese Patent Application Laid-Open (KOKAI) Nos. 61-148154(1986), 63-141980(1988),63-225358(1988), 63-238063(1988), 63-239271(1988),63-284175(1988), 63-297367(1988), 64-73(1989) and 1-132566(1989), EP-A-268871 and International Publication of PCT 88/02256 report that a particular derivative of 9-aminotetrahydroacridine has an antiacetylcholinesterase activity and is therefore useful for treatment of Alzheimer's disease.
Summers reports in The New England Journal of Medicine, 315, 1241(1986) that 9-amino-1,2,3,4-tetrahydroacridine (tacrine) is effective for treatment of Alzheimer's disease when used together with lecithin. However, improvement is still insufficient and it produces undesirable side effects, and therefore, a new therapeutic treatment has been demanded.
As examples of the known 9-acylaminotetrahydroacridines, 9-acetylanminotetrahydroacridine is described in Journal of Chemical Society, 634(1947) and 9-chloroacetylaminotetrahydroacridine and 9-diethylaminoacetylaminotetrahycdroacridine are described in Chem. listy, 51, 1907(1957). 9-Diethylanminoacetylaminotetrahydroacridine is described to have a local anesthetic action. In Journal of Medicinal Chemistry, 18, 1056(1975), structure-activity correlation on antiacetylcholinesterase activity of 9-aminotetrahydroacridine derivatives and it is reported that the activity of 9-acetylaminotetrahydroacridine and 9-benzoylaminotetrahydroacridine is 1/1000 of the activity of 9-aminotetrahydroacridine. Some of Japanese Patent Application Laid-Open (KOKAI) Nos. 63-166881(1988), 63-203664(1988), 63-238063(1988), 63-239271(1988), 63-284175(1988), 64-73(1989) and 1-132566(1989) claims a 9-acylaminotetrahydroacridine derivative, however, none of them disclose expressly the synthesis of nor a pharmaceutical activity of a compound having a 9-acylamino group.
The present inventors have made various and extensive studies so as to provide a medicine effective for treatment of senile dementia including Alzheimer's disease. As the result thereof, it has been found that a particular 4-acylaminopyridine derivative and a pharmaceutically acceptable acid-added salt thereof can improve disturbances of memory such as Alzheimer's disease by a mechanism different from that of a conventionally known compound having an antiacetylcholinesterase activity. The present invention has been accomplished based on this finding.